Relationship between membrane phosphatidylinositol-4,5-bisphosphate and receptor-mediated inhibition of native neuronal M channels

The relationship between receptor-induced membrane phosphatidylinositol-4'5'-bisphosphate (PIP2) hydrolysis and M-current inhibition was assessed in single-dissociated rat sympathetic neurons by simultaneous or parallel recording of membrane current and membrane-to-cytosol translocation of the fluorescent PIP2/inositol 1,4,5-trisphosphate (IP3)-binding peptide green fluorescent protein-tagged pleckstrin homology domain of phospholipase C (GFP-PLC delta-PH). The muscarinic receptor agonist oxotremorine-M produced parallel time- and concentration-dependent M-current inhibition and GFP-PLC delta-PH translocation; bradykinin also produced parallel time- dependent inhibition and translocation. Phosphatidylinositol-4-phosphate-5-kinase (PI5-K) overexpression reduced both M-current inhibition and GFP-PLC delta-PH translocation by both oxotremorine-M and bradykinin. These effects were partly reversed by wortmannin, which inhibits phosphatidylinositol-4-kinase (PI4-K). PI5-K overexpression also reduced the inhibitory action of oxotremorine-M on PIP2-gated G-protein-gated inward rectifier (Kir3.1/3.2) channels; bradykinin did not inhibit these channels. Overexpression of neuronal calcium sensor-1 protein (NCS-1), which increases PI4-K activity, did not affect responses to oxotremorine-M but reduced both fluorescence translocation and M-current inhibition by bradykinin. Using an intracellular IP3 membrane fluorescence-displacement assay, initial mean concentrations of membrane [PIP2] were estimated at 261 mu M (95% confidence limit; 192-381 mu M), rising to 693 mu M (417-1153 mu M) in neurons overexpressing PI5-K. Changes in membrane [PIP2] during application of oxotremorine-M were calculated from fluorescence data. The results, taken in conjunction with previous data for KCNQ2/3 (Kv7.2/Kv7.3) channel gating by PIP2 (Zhang et al., 2003), accorded with the hypothesis that the inhibitory action of oxotremorine-M on M current resulted from depletion of PIP2. The effects of bradykinin require additional components of action, which might involve IP3-induced Ca2+ release and consequent M-channel inhibition (as proposed previously) and stimulation of PIP2 synthesis by Ca2+-dependent activation of NCS-1

Estrogen Receptor and Signal Transducer and Activator of Transcription 3 Expression in Equine Mammary Tumors.

Equine mammary tumors are uncommon, and relatively sparse histopathologic and molecular data exist. The present study describes the histopathologic features of 7 such tumors, which exhibited infiltrative growth, intermediate to high mitotic rates, and focally extensive necrosis. The tumors exhibited variably strong staining for vimentin and cytokeratin 14, as well as frequently weak cytoplasmic staining for pan-cytokeratin. E-cadherin expression was strong. Interestingly, a subgroup of the tumors exhibited strong nuclear staining for estrogen receptor α. Three of 7 tumors exhibited nuclear expression of the transcription factor STAT3, suggesting that STAT3 was transcriptionally active. Rare to absent nuclear STAT3 expression was observed in carcinomas exhibiting moderate to intense staining for cytokeratin 14. This investigation confirms previous investigators' assertions that equine mammary tumors have a malignant phenotype. A subset of the equine mammary tumors exhibited estrogen receptor α expression, suggesting that these tumors may potentially have similar molecular characteristics to their feline and canine counterparts.This is the author accepted manuscript. The final version is available from Sage via http://dx.doi.org/10.1177/030098581455940

Birthweight, childhood growth and left ventricular structure at age 60-64 years in a British birth cohort study

Background: High left ventricular mass (LVM) is an independent predictor of cardiovascular disease and mortality, but information relating LVM in older age to growth in early life is limited. We assessed the relationship of birthweight, height and body mass index (BMI) and overweight across childhood and adolescence with later life left ventricular (LV) structure. Methods: We used data from the MRC National Survey of Health and Development (NSHD) on men and women born in 1946 in Britain and followed up ever since. We use regression models to relate prospective measures of birthweight and height and BMI from ages 2–20 years to LV structure at 60–64 years. Results: Positive associations of birthweight with LVM and LV end diastolic volume (LVEDV) at 60–64 years were largely explained by adult height. Higher BMI, greater changes in BMI and greater accumulation of overweight across childhood and adolescence were associated with higher LVM and LVEDV and odds of concentric hypertrophy. Those who were overweight at two ages in early life had a mean LVM 11.5 g (95% confidence interval: -2.19,24.87) greater, and a mean LVEDV 10.0 ml (3.7,16.2) greater, than those who were not overweight. Associations were at least partially mediated through adult body mass index. Body size was less consistently associated with relative wall thickness (RWT), with the strongest association being observed with pubertal BMI change [0.007 (0.001,0.013) per standard deviation change in BMI 7–15 years]. The relationships between taller childhood height and LVM and LVEDV were explained by adult height. Conclusions: Given the increasing levels of overweight in contemporary cohorts of children, these findings further emphasize the need for effective interventions to prevent childhood overweight

Hyperglycemia Has a Greater Impact on Left Ventricle Function in South Asians Than in Europeans

OBJECTIVE Diabetes is associated with left ventricular (LV) diastolic and systolic dysfunction. South Asians may be at particular risk of developing LV dysfunction owing to a high prevalence of diabetes. We investigated the role of diabetes and hyperglycemia in LV dysfunction in a community-based cohort of older South Asians and white Europeans. RESEARCH DESIGN AND METHODS Conventional and Doppler echocardiography was performed in 999 participants (542 Europeans and 457 South Asians aged 58–86 years) in a population-based study. Anthropometry, fasting bloods, coronary artery calcification scoring, blood pressure, and renal function were measured. RESULTS Diabetes and hyperglycemia across the spectrum of HbA1c had a greater adverse effect on LV function in South Asians than Europeans (N-terminal-probrain natriuretic peptide β ± SE 0.09 ± 0.04, P = 0.01, vs. −0.04 ± 0.05, P = 0.4, P for HbA1c/ethnicity interaction 0.02), diastolic function (E/e′ 0.69 ± 0.12, P < 0.0001, vs. 0.09 ± 0.2, P = 0.6, P for interaction 0.005), and systolic function (s′ −0.11 ± 0.06, P = 0.04, vs. 0.14 ± 0.09, P = 0.1, P for interaction 0.2). Multivariable adjustment for hypertension, microvascular disease, LV mass, coronary disease, and dyslipidemia only partially accounted for the ethnic differences. Adverse LV function in diabetic South Asians could not be accounted for by poorer glycemic control or longer diabetes duration. CONCLUSIONS Diabetes and hyperglycemia have a greater adverse effect on LV function in South Asians than Europeans, incompletely explained by adverse risk factors. South Asians may require earlier and more aggressive treatment of their cardiometabolic risk factors to reduce risks of LV dysfunction

The association between region of birth and sexually transmitted infections among people of black Caribbean ethnicity attending sexual health services in England, 2015.

BACKGROUND/INTRODUCTION: In England, people of Black Caribbean (BC) ethnicity are disproportionately affected by sexually transmitted infections (STIs), but it is unclear whether this varies by their region of birth. AIM(S)/OBJECTIVES: To examine differences in STI diagnoses among UK- and Caribbean-born BC people. METHODS: Data on STI diagnoses in BC people attending specialist sexual health services (SHSs) during 2015 and living in England were obtained from the GUMCAD STI surveillance system, the national surveillance system for STIs in England. Associations between being UK- or Caribbean-born and each of several STI diagnoses were examined, using univariate and multivariable generalised estimated equations logistic regression models adjusted for sexual orientation, place of residence (London vs. non-London), HIV status, area-level deprivation, and STI diagnosis in the last year. All analyses were stratified by age (<25 vs. ≥25 years). RESULTS: In 2015, 63,568 BC people made 108,881 attendances at specialist SHSs; 81.9% of these attendances were made by UK-born BCs. The median age (years) was 26 for UK-born and 35 for Caribbean-born people (p≤0.001). Chlamydia, gonorrhoea and non-specific genital infection (NSGI) were the most commonly diagnosed STIs among UK- (5.8%, 2.1% and 2.8%) and Caribbean-born people (4.5%, 1.7% and 3.5%) respectively. Among BCs aged under 25, no significant differences in STIs were found between UK- and Caribbean-born people. Among BCs aged ≥25, compared to Caribbean-born people, those who were UK-born were more likely to be diagnosed with chlamydia (AOR 1.15 [95%C.I. 1.04-1.27]); gonorrhoea (AOR 1.23 [95%C.I. 1.06-1.45]) and genital herpes (AOR 1.23 [95% C.I. 1.10-1.56]) and less likely to be diagnosed with NSGI (AOR 0.89 [95% C.I. 0.80-0.99]) and Trichomoniasis (AOR 0.84 [95% C.I. 0.71-0.99]). DISCUSSION/CONCLUSION: STI diagnoses in BC people aged ≥25 attending specialist SHSs vary by region of birth. Country of birth may have an influence on social and sexual networks and therefore transmission of STIs

Cardiovascular Risk Factors from Early Life Predict Future Adult Cardiac Structural and Functional Abnormalities: A Systematic Review of the Published Literature

Background: Clinical practice evaluates cardiovascular risk based on current risk factor (RF) levels [Blood pressure (BP), body mass index (BMI) and glycaemic control] largely disregarding previous risk-factor history over the totality of the life course. RFs are related to contemporaneous echocardiographic measures of cardiac structure and function which in turn are independently related to cardiovascular morbidity and mortality in cross-sectional studies. However, the effect of lifetime or earlier RF history on future echocardiographic changes has never been systematically examined. Methods: A systematic review of the published literature identified 24 studies relating either earlier BP, BMI, glycaemic control or a combination to future cardiac structure and/or function. Results: The majority of studies showed that elevated BP and BMI in earlier life and greater cumulative burden of these factors resulted in worse cardiac structure up to 24 years later. Studies examining glycaemic control as a RF were few, but poorer glycaemic control in young adults was associated with increased future left ventricular mass. While only 5 papers related RFs to future cardiac function, all RFs were positively associated with worse future diastolic function. Conclusions: BP, BMI and glycaemic control measures in childhood, adolescence and early adulthood and subsequent longitudinal trajectories of BP and BMI are predictive of future abnormalities in cardiac structure and function. Lifetime RF history should be used to inform clinical practice. Further research is required to enable the identification of any sensitive periods in the life course to enable prevention when it is most likely to be effective

Quality of Life with Late-Onset Pompe Disease: Qualitative Interviews and General Public Utility Estimation in the United Kingdom

Background: Late-onset Pompe disease (LOPD) is a rare, progressive neuromuscular condition typically characterized by weakness of skeletal muscles, including those involved in respiration and diaphragmatic dysfunction. Individuals with LOPD typically eventually require mobility and/or ventilatory support. / Objectives: This study aimed to develop health state vignettes and estimate health state utility values for LOPD in the United Kingdom. / Methods: Vignettes were developed for 7 health states of LOPD with states defined in terms of mobility and/or ventilatory support. Vignettes were drafted based on patient-reported outcome data from the Phase 3 PROPEL trial (NCT03729362) and supplemented by a literature review. Qualitative interviews with individuals living with LOPD and clinical experts were conducted to explore the health-related quality-of-life (HRQoL) impact of LOPD and to review the draft vignettes. Vignettes were finalized following a second round of interviews with individuals living with LOPD and used in health state valuation exercises with people of the UK population. Participants rated the health states using the EQ-5D-5L, visual analog scale, and time trade-off interviews. / Results: Twelve individuals living with LOPD and 2 clinical experts were interviewed. Following the interviews, 4 new statements were added regarding dependence on others, bladder control problems, balance issues/fear of falling, and frustration. One hundred interviews with a representative UK population sample were completed. Mean time trade-off utilities ranged from 0.754 (SD = 0.31) (no support) to 0.132 (SD = 0.50) (invasive ventilatory and mobility support-dependent). Similarly, EQ- 5D-5L utilities ranged from 0.608 (SD = 0.12) to -0.078 (SD = 0.22). / Discussion: The utilities obtained in the study are consistent with utilities reported in the literature (0.670-0.853 for nonsupport state). The vignette content was based on robust quantitative and qualitative evidence and captured the main HRQoL impacts of LOPD. The general public rated the health states consistently lower with increasing disease progression. There was greater uncertainty around utility estimates for the severe states, suggesting that participants found it harder to rate them. / Conclusion: This study provides utility estimates for LOPD that can be used in economic modeling of treatments for LOPD. Our findings highlight the high disease burden of LOPD and reinforce the societal value of slowing disease progression

The relationship between pubertal timing and markers of vascular and cardiac structure and function in men and women aged 60-64 years

Earlier age at menarche has been associated with higher risk of coronary heart disease, but the mechanisms underlying the association remain unclear. We assessed the relationship of pubertal timing, in both men (n = 672) and women (n = 713), with vascular (carotid intima-media thickness (cIMT), pulse wave velocity (PWV)) and cardiac (left ventricular (LV) structure and function) measures recorded at age 60-64 yrs in a British birth cohort study. Regression models found that earlier menarche was associated with higher (more adverse) LV mass, LV end diastolic volume and left atrial volume, but not with other cardiac measures, cIMT or PWV. Associations were attenuated after adjustment for either adult or childhood BMI (e.g. mean difference in LV mass per year later menarche: -4.2 g (95% CI:-7.0,-1.4) reducing to -2.2 g (95% CI:-4.7,0.4) after adjustment for adult BMI). There were no associations among men, despite those fully mature at 15 yrs having higher blood pressure than the least mature group by 10.21 mmHg (95% CI:19.45,0.98). Any effect of pubertal timing on vascular and cardiac structure and function is likely to be small and primarily confounded by pre-pubertal BMI and/or mediated through adult adiposity

The PdBI Arcsecond Whirlpool Survey (PAWS): Multi-phase cold gas kinematic of M51

This is the final version of the article. Available from the publisher via the DOI in this record.The kinematic complexity and the favorable position of M51 on the sky make this galaxy an ideal target to test different theories of spiral arm dynamics. Taking advantage of the new high-resolution PdBI Arcsecond Whirlpool Survey data, we undertake a detailed kinematic study of M51 to characterize and quantify the origin and nature of the non-circular motions. Using a tilted-ring analysis supported by several other archival data sets, we update the estimation of M51's position angle (P.A. = (173 ± 3)°) and inclination (i = (22 ± 5)°). Harmonic decomposition of the high-resolution (∼40 pc) CO velocity field shows the first kinematic evidence of an m = 3 wave in the inner disk of M51 with a corotation at R CR, m = 3 = 1.1 ± 0.1 kpc and a pattern speed of Ωp, m = 3 ≈ 140 km s -1 kpc-1. This mode seems to be excited by the nuclear bar, while the beat frequencies generated by the coupling between the m = 3 mode and the main spiral structure confirm its density-wave nature. We observe also a signature of an m = 1 mode that is likely responsible for the lopsidedness of M51 at small and large radii. We provide a simple method to estimate the radial variation of the amplitude of the spiral perturbation (V sp) attributed to the different modes. The main spiral arm structure has 〈V sp〉 = 50-70 km s-1, while the streaming velocity associated with the m = 1 and m = 3 modes is, in general, two times lower. Our joint analysis of H I and CO velocity fields at low and high spatial resolution reveals that the atomic and molecular gas phases respond differently to the spiral perturbation due to their different vertical distribution and emission morphology. © 2014. The American Astronomical Society. All rights reserved.We thank our anonymous referee for thoughtful comments that improved the quality of the paper. We thank the IRAM staff for their support during the observations with the Plateau de Bure interferometer and the 30 m telescope. D.C. and A.H. acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG) via grant SCHI 536/5-1 and SCHI 536/7-1 as part of the priority program SPP 1573 “ISM-SPP: Physics of the Interstellar Medium.” C.L.D. acknowledges funding from the European Research Council for the FP7 ERC starting grant project LOCALSTAR. T.A.T. acknowledges support from NASA grant No. NNX10AD01G. During this work, J.P. was partially funded by the grant ANR-09-BLAN-0231-01 from the French Agence Nationale de la Recherche as part of the SCHISM project (http://schism.ens.fr/). E.S., A.H. and D.C. thank NRAO for their support and hospitality during their visits in Charlottesville. E.S. thanks the Aspen Center for Physics and the NSF grant No. 1066293 for hospitality during the development and writing of this paper. D.C. thanks Glenn van de Ven for the useful discussion and the help with the harmonic decomposition code. S.G.B. acknowledges economic support from Junta de Andalucia grant P08 TIC 03531. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc

Midlife blood pressure predicts future diastolic dysfunction independently of blood pressure

OBJECTIVES: High blood pressure (BP) is associated with diastolic dysfunction, but the consequence of elevated BP over the adult life course on diastolic function is unknown. We hypothesised that high BP in earlier adulthood would be associated with impaired diastolic function independent of current BP. METHODS: Participants in the Medical Research Council National Survey of Health and Development birth cohort (n=1653) underwent investigations including echocardiography at age 60-64 years. The relationships between adult BP, antihypertensive treatment (HTT) and echocardiographic measures of diastolic function were assessed using adjusted regression models. RESULTS: Increased systolic BP (SBP) at ages 36, 43 and 53 years was predictive of increased E/e' and increased left atrial volume. These effects were only partially explained by SBP at 60-64 years and increased left ventricular mass. HTT was also associated with poorer diastolic function after adjustment for SBP at 60-64 years. Faster rates of increase in SBP in midlife were also associated with increased poorer diastolic function. CONCLUSIONS: High SBP in midlife is associated with poorer diastolic function at age 60-64 years. Early identification of individuals with high BP or rapid rises in BP may be important for prevention of impaired cardiac function in later life